The invention relates to the treatment of Parkinson's disease, sexual dysfunction, stroke, and depressive disorders, and to the diagnosis of conditions associated with abnormal D2 receptor function.
Dopamine is unarguably one of the most important neurotransmitters in the brain. Disturbances in the dopaminergic system, and especially irregularities in dopamine D2 receptor function, have been implicated in many different neurological and psychiatric disorders, including Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit-hyperactivity disorder, Tourette's syndrome, restless leg syndrome, and addiction (see Bozzi, et al., TRENDS in Neurosciences 29:167 (2006); and Marsden, C. A. British J. Pharm. 147:S136 (2006)). Early diagnosis of these disorders is desirable, as early treatment of the disease would allow for a better outcome for the patient, by slowing the progression of the disease and lessening the severity of the symptoms or future episodes. Physical symptoms tend to manifest themselves much later, after significant changes occur in the brain. Thus, identification of subtle changes in the brain early in the course of the disease, before a clinical diagnosis from physical symptoms can be made, would offer the best opportunity for early treatment.
Parkinson's disease is a progressive neurodegenerative disorder of the basal ganglia of the brain, which most often becomes apparent after the age of 55. It is a prevalent and prototypic hypokinetic disorder, with akinesia, bradykinesia, rigidity and tremor as the most prominent features. The neurological and psychiatric symptoms, including depression and psychosis, with late dementia, usually worsen with time. The neuropathology of Parkinson's disease reveals a striking and selective loss of the dopaminergic neurons of the nigrostriatal pathway of the brain.
As Parkinson's disease is associated with a loss of the neurotransmitter dopamine, it is commonly treated with drugs which replace or mimic the actions of dopamine. Since dopamine itself cannot pass the blood-brain diffusion barrier, the most commonly used therapy is levodopa (L-DOPA), the immediate precursor of dopamine which is readily decarboxylated by remaining dopaminergic neurons and other amine-producing neurons. A complication of long-term treatment with L-DOPA is the development of rapid fluctuations in clinical state such that the patient changes, often abruptly, between mobility and immobility; this phenomenon is known as the ‘on-off’ effect.
An alternative approach to treatment with L-DOPA is the use of drugs (dopamine agonists and partial-agonists) that mimic the actions of dopamine. Treatment with dopamine receptor agonists has some advantages over treatment with L-DOPA. Unlike L-DOPA, dopamine agonists are effective in patients with advanced stages of Parkinson's disease because their action at postsynaptic receptors is unaffected by the lack of dopamine producing nerve cells that decarboxylate L-DOPA to produce dopamine locally, whereas the denervated dopamine receptors are supersensitive to agonists. Furthermore, there is an increasing interest in the potential of dopamine receptor agonists to provide a neuroprotective effect. Theoretically, such a protective effect might result from (i) a decreased need for the use of L-DOPA, a substance that may cause oxidative stress and perhaps even contribute to further damage of dopamine neurons, (ii) stimulation of dopamine autoreceptors resulting in decreased dopamine synthesis, release, and turnover, resulting in reduced metabolism of dopamine to reactive oxygen species, and (iii) by direct anti-oxidant effects.
R(−)-Apomorphine is a directly acting dopamine agonist at both D1 and D2 receptors, and dopamine autoreceptors, without opiate-like or addictive properties. Apomorphine therapy has led to sustained improvements in Parkinson's disease patients with refractory motor oscillations (on-off phenomena). However, it is difficult to administer owing to its poor bioavailability and extensive first-pass metabolism to inactive metabolites. Therefore, apomorphine is usually administered either by intermittent subcutaneous injection or continuous subcutaneous infusion. Following a single dose, apomorphine has an onset of action of 5-15 minutes, and its effects last for 40-60 minutes.
Direct dopamine agonists, including R(−)-apomorphine, are also effective in the treatment of a number of forms of sexual dysfunction, primarily, but not limited to erectile dysfunction. See Martinez et al., J. Urology 170:2352 (2003).
There are two general classes of dopamine receptors in the brain, type D1, which interacts with the Gs complex to activate adenylyl cyclase, and type D2, which interacts with Gi to inhibit cAMP production. Among these two classes exist at least five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. The D1 and D5 receptors have a D1-like pharmacology, whereas the D2, D3, and D4 receptors have a D2-like pharmacological profile. The dopamine receptors are part of the general family of G protein-linked receptors. A receptor which is linked to a G protein (of which there are many types) can exist in two states. These two states are referred to as the high affinity state and low affinity state. For example, in the case of the dopamine receptor, dopamine has a dissociation constant of 1.5 nM for the high-affinity state, or D2High, and approximately 200-2000 nM for the low-affinity state, or D2Low. Depending on local conditions in vitro or in vivo, the two states can quickly convert into each other. Because the high-affinity state is considered the functional state (George et al., Endocrinology 117: 690, 1985), the process of “desensitization” occurs whenever the high-affinity state converts into the low-affinity state.
Noninvasive imaging of molecular and biological processes in living subjects with positron emission tomography (PET) and single photon emission computed tomography (SPECT) are invaluable tools for the investigation of human neurochemistry and neuropharmacology in vivo (see, for example, Ametamey et al., Chem. Rev. 108:1501 (2008)). Extensive research efforts have been directed toward the development of PET and SPECT radioligands suitable for probing the dopaminergic system (see Abi-Dargham et al., J. Nucl. Med. 37:1129 (1996); Seibyl et al., J. Nucl. Med. 39:1500 (1998); Neumeyer et al., J. Med. Chem. 34:3144 (1991); Innis et al., Proc. Natl. Acad. Sci. USA. 90:11965 (1993); and Airaksinen, et al., Bioorg. Med. Chem. 16:6467 (2008).
Previous studies suggest that in certain neurological disorders, such as schizophrenia and other DA-dependent neurological disorders, more D2 receptors exist in the D2high state (see Seeman, P. Clin. Schizophrenia and Related Psychoses 351-355 (2008); Seeman et al., Proc. Natl. Acad. Sci. 102:3513 (2005); Seeman, P. Synapse 63:186 (2009) and Seeman, P. Synapse 62:314 (2008)), and that D2high is the primary and common target for the antiparkinson action of dopamine agonists (see Seeman, P. Synapse 61:1013 (2007); Seeman et al., Synapse 58:122 (2005).
New compounds that discriminate between high affinity (D2high) and low affinity (D2low) states of the D2 receptor are needed for the treatment and diagnosis of diseases, such as Parkinson's disease and schizophrenia.